Nitric Oxide Induced stx2 Expression Is Inhibited by the Nitric Oxide Reductase, NorV, in a Clade 8 Escherichia coli O157:H7 Outbreak Strain

Escherichia coli O157:H7 pathogenesis is due to Shiga toxin (Stx) production, though variation in virulence has been observed. Clade 8 strains, for instance, were shown to overproduce Stx and were more common among hemolytic uremic syndrome cases. One candidate gene, norV, which encodes a nitric oxide (NO) reductase found in a clade 8 O157:H7 outbreak strain (TW14359), was thought to impact virulence. Hence, we screened for norV in 303 O157 isolates representing multiple clades, examined stx2 expression following NO exposure in TW14359 for comparison to an isogenic mutant (ΔnorV), and evaluated survival in THP-1 derived macrophages. norV was intact in strains representing clades 6–9, whereas a 204 bp deletion was found in clades 2 and 3. During anaerobic growth, NO induced stx2 expression in TW14359. A similar increase in stx2 expression was observed for the ΔnorV mutant in anaerobiosis, though it was not impaired in its ability to survive within macrophages relative to TW14359. Altogether, these data suggest that NO enhances virulence by inducing Stx2 production in TW14359, and that toxin production is inhibited by NorV encoded by a gene found in most clade 8 strains. The mechanism linked to these responses, however, remains unclear and likely varies across genotypes.

HPV and Recurrent Respiratory Papillomatosis: A Brief Review

Recurrent Respiratory Papillomatosis (RRP) is a rare but severe manifestation of human papillomavirus (HPV). As our knowledge about HPV infections has expanded, it has become possible to understand the course of RRP disease and unravel plausible efficient methods to manage the disease. However, the surge in reports on HPV has not been accompanied by a similar increase in research about RRP specifically. In this paper, we review the clinical manifestation and typical presentation of the illness. In addition, the pathogenesis and progression of the disease are described. On the other hand, we discuss the types of treatments currently available and future treatment strategies. The role of vaccination in both the prevention and treatment of RRP will also be reviewed. We believe this review is essential to update the general knowledge on RRP with the latest information available to date to enhance our understanding of RRP and its management.

Heat Waves and Innovation in Air Conditioning in the United States

This study investigates whether extreme heat episodes (heatwaves) have contributed to the development of air conditioning technology in the United States. To this end we use weather data to identify days at which heat and relative humidity were above levels comfortable to the human body, and match these with patent data at the county level for nearly a hundred years. We find that in the two years after a county has experienced extreme heat air-conditioning patents increase. Overall, average extreme heat exposure results in an increase of 7.5% greater innovation. We find no similar increase in the frequency of non-air conditioning related patent filings, and therefore conclude that heatwaves result in innovation targeting their mitigation.

Increased risk of thyroid dysfunction by PD-1 and CTLA-4 blockade in patients without thyroid autoantibodies at baseline

Background Previous studies showed that although the risk of thyroid dysfunction (thyroid immune-related adverse events [irAEs]) induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2–7% in patients negative for anti-thyroid-antibodies (ATAs) at baseline, it was much higher (30–50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. Methods A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab plus CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the last clinical visit. Results Of the 451 patients, 51 developed thyroid-irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) with CTLA-4-Ab, and 10 of 27 (37.0%) with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid-irAEs was significantly higher in patients who were positive versus negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs. 13/329 (4.0%), p < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs. 4/17 (23.5%), p < 0.05] treatments. The risk of thyroid-irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. Conclusions This study showed that the incidence of thyroid-irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

The Oxford Domed Lateral Unicompartmental Knee Replacement implant: Increasing wall height reduces the risk of bearing dislocation

Due to lateral ligament laxity, bearing dislocation occurs in 1%–6% of Oxford Domed Lateral replacements. Most dislocations are medial but they do rarely occur anteriorly or posteriorly. The aim was to decrease the risk of dislocation. For a bearing to dislocate the femoral component has to be distracted from the tibial component. A robotic-path-planning-algorithm was used with a computer model of the implant in different configurations to determine the Vertical Distraction needed for Dislocation (VDD). With current components, VDD anteriorly/posteriorly was 5.5 to 6.5 mm and medially was 3.5 to 5.75 mm. A thicker bearing increased VDD medially and decreased VDD anteriorly/posteriorly (0.1 mm/1 mm thickness increase). VDD medially increased with the bearing closer to the tibial wall (0.5 mm/1 mm closer), or by increasing the tibial wall height (1 mm/1 mm height increase). VDD anteriorly/posteriorly was not influenced by bearing position or wall height. To prevent collision between the femoral and tibial components an increase in wall height must be accompanied by a similar increase in minimum bearing thickness. Increasing the wall height and minimum bearing thickness by 2 mm and ensuring the bearing is 4 mm or less from the wall increased the minimum VDD medially to 5.5 mm. The lower VDD medially than anteriorly/posteriorly explains why medial dislocation is more common. If the wall height is increased by 2 mm, the minimum bearing thickness is 5 mm and the surgeon ensured the bearing is 4 mm or less from the wall, the medial dislocation rate should be similar to the anterior/posterior dislocation rate, which should be acceptable.

Nuclear morphogenesis: forming a heterogeneous nucleus during embryogenesis

An embryo experiences progressively complex spatial and temporal patterns of gene expression that guide the morphogenesis of its body plan as it matures. Using super-resolution fluorescence microscopy in Drosophila melanogaster embryos, we observed a similar increase in complexity in the nucleus: the spatial distributions of transcription factors became increasingly heterogeneous as the embryo matured. We also observed a similar trend in chromatin conformation with the establishment of specific histone modification patterns. However, transcription sites of specific genes had distinct local preferences for histone marks separate from the average nuclear trend, depending on the time and location of their expression. These results suggest that reconfiguring the nuclear environment is an integral part of embryogenesis and that the physical organization of the nucleus a key element in developmental gene regulation.

Impact of preoperative exercise in not initially candidates to native arteriovenous fistulas

Background: Native autologous arteriovenous fistula (AVFn) is the preferred vascular access for hemodialysis due to its long term patency and low complication rate. A challenging limitation is the anatomical inability to perform AVFn and failure of maturation. Preoperative isometric exercise (PIE) can increase vascular calibers and improve the rate of distal AVF. However, it is unknown whether PIE might enhance the performance of AVFn in patients who are not initially candidates. Methods: A retrospective observational study was conducted over a population of 45 patients evaluated in vascular access clinic, 23 were not initially candidates for radiocephalic (NRC-AVF) and 22 were not candidates for autologous fistula at all (NA-AVF). They were assigned to perform PIE with handgrip device and revaluated. Results: After 4–8 weeks of PIE, a AVFn was performed in 16 patients from NA-AVF group and a radiocephalic AVFn was performed in 21 patients from NRC-AVF group. Both groups experienced a significant and similar increase in venous caliber 0.91 ± 0.43 mm in NA-AVF versus 0.76 ± 0.47 mm in NRC-AVF ( p = 0.336) and arterial caliber 0.18 ± 0.24 mm versus 0.18 ± 0.21 mm ( p = 0.928), respectively. Nevertheless, primary failure rate was significantly higher in NA-AVF ( n = 8, 50%) than in NRC-AVF group ( n = 3, 14.3%) ( p = 0.030). After 6 months, the fistula usability for dialysis was only 50% in NA-AVF, while 86.7% were dialyzed by fistula in NRC-AVF group ( p = 0.038). Conclusions: PIE allowed the allocation of an AVFn in patients not initially candidates, but entailed a high rate of maturation failure. Patients not candidates to radiocephalic AVF benefited from PIE and preserved a long term usability of AVF for dialysis.

Trace Amine-Associated Receptor 1 Contributes to Diverse Functional Actions of O-Phenyl-Iodotyramine in Mice but Not to the Effects of Monoamine-Based Antidepressants

Trace Amine-Associated Receptor 1 (TAAR1) is a potential target for the treatment of depression and other CNS disorders. However, the precise functional roles of TAAR1 to the actions of clinically used antidepressants remains unclear. Herein, we addressed these issues employing the TAAR1 agonist, o-phenyl-iodotyramine (o-PIT), together with TAAR1-knockout (KO) mice. Irrespective of genotype, systemic administration of o-PIT led to a similar increase in mouse brain concentrations. Consistent with the observation of a high density of TAAR1 in the medial preoptic area, o-PIT-induced hypothermia was significantly reduced in TAAR1-KO mice. Furthermore, the inhibition of a prepulse inhibition response by o-PIT, as well as its induction of striatal tyrosine hydroxylase phosphorylation and elevation of extracellular DA in prefrontal cortex, were all reduced in TAAR1-KO compared to wildtype mice. O-PIT was active in both forced-swim and marble-burying tests, and its effects were significantly blunted in TAAR1-KO mice. Conversely, the actions on behaviour and prefrontal cortex dialysis of a broad suite of clinically used antidepressants were unaffected in TAAR1-KO mice. In conclusion, o-PIT is a useful tool for exploring the hypothermic and other functional antidepressant roles of TAAR1. By contrast, clinically used antidepressants do not require TAAR1 for expression of their antidepressant properties.

An analytical stress model for composite multi-pinned plates considering the combination effects of pin load and bypass load in different positions

Multi-pin joints are commonly used in engineering due to their high loading capacity. However, affected by coupling relationships between pin load and bypass load, the evaluation of stress state is difficult for composite multi-pin joints. An analytical method is proposed in this paper to calculate stress distribution of these joints under tensile load. Stress functions in this method are created considering the pin load and bypass load, according to a geometry division of the whole plate. Superposition relationships are built for each section type with an influence coefficient of bypass load. Stress components could be obtained by calculation of stress functions when material properties, geometry dimension and load are known. Experiments and finite element method are employed to verify the validation of proposed method. Results show that pin position affects stress state, and mainly embodies in σx. The first pin always gets the highest stress level, while for the other pins the stress is quite similar. Increase pin number will decrease stress level but the effect is relatively small for the first pin.

Cu-ZnO Nanostructures Synthesis and Characterization

5wt% copper doped zinc oxide (Cu-ZnO) nanostructures were prepared via the hydrothermal technique at different temperatures of 70, 100, 130, 160 and 190oC. UV spectroscopy, FE-SEM microscopy, XRD crystallography, and EDS measurements were used for nanostructure characterization. UV spectroscopy indicated a red shift for the absorption peaks, and hence a blue shift for the energy gap values, as temperature increased from 70 to 190oC. FE-SEM microscopy showed an increase in the average lengths and diameters of the nanostructures following a similar increase in temperature. XRD crystallography indicated decent structural patterns for Cu-ZnO nanostructures with an increase in crystallite size upon temperature increase. Interestingly, three unprecedented extra indices appeared in the structural pattern at 190oC, which might indicate a configuration of hexagonal crystallite with three extra planes. EDS measurements indicated the sole presence of Cu, Zn and O.